The study, led by James E. Haddow, MD, of the Foundation for Blood Research in Scarborough, Maine, was funded by the National Institute of Child Health and Human Development.
The screening technique makes use of two substances, or markers, for Down syndrome that tend to appear in abnormal amounts in the blood of women carrying fetuses with Down syndrome. Down syndrome, also sometimes referred to as Trisomy 21, is a genetic abnormality resulting from either an extra copy of chromosome 21 or from an extra portion of the long arm of the chromosome. The risk of the condition increases sharply with maternal age. For women under age 30, the risk of conceiving a fetus with Down syndrome is less than 1 in 1,000. By age 35, the risk is 1 in 400, by age 40, 1 in 105, and by age 49, 1 in 12.
Currently, the most effective way to diagnose fetuses with Down syndrome between the 9th and 12th week of pregnancy (during the first trimester) is with a procedure known as chorionic villus sampling (CVS). In this procedure, a needle is inserted into the uterus, either through the abdomen or the cervix, and a sample is extracted from the chorionic villi, the tissue which will later become the placenta. Dr. Haddow explained that this sampling technique, however, carries a one to two percent risk of miscarriages. He added that a reliable test that did not involve removing fetal tissue samples from the uterus would avoid the attendant risk of miscarriage.
Amniocentesis, a technique similar to chorionic villus sampling, is also occasionally used to diagnose Down syndrome in the first trimester but is usually not performed until after the beginning of the second trimester, after the 14th week of pregnancy. Amniocentesis involves inserting a needle into the uterus to withdraw fetal cells from the amniotic fluid, for later chromosomal analysis. The procedure carries with it a 0.5 percent risk of miscarriage.
Because of the invasiveness, risk, and cost of cvs and amniocentesis, scientists have sought ways to screen pregnancies with simpler tests that would provide an indication of women with a higher liklihood of carrying a fetus with Down syndrome. These higher risk women could then be offered the diagnostic procedures of CVS or amniocentesis. Currently, screening for Down syndrome takes place during the second trimester of pregnancy and involves testing for alpha-fetoprotein, unconjugated estriol, as well as human chorionic gonadotropin. This study extends screening to the first trimester.
Women with abnormal levels of these substances are usually then referred for diagnosis by amniocentesis. For the study, Dr. Haddow and his coworkers collected blood samples from a total of 4,412 pregnant women at 16 prenatal diagnostic centers in the United States. The researchers then analyzed the samples for various substances often found in abnormal levels in the blood of women pregnant with a fetus with Down syndrome. Among the substances for which the researchers tested were: human chorionic gonadotropin (hCG); a portion of the hCG molecule, known as the free beta subunit of hCG; and pregnancy-associated protein A. Smaller studies conducted previously have shown that both hCG levels and levels of the beta subunit of hCG are higher in the presence of a fetus with Down syndrome than in a fetus with a normal chromosome count. Conversely, blood levels of protein A are lower than normal in the presence of a fetus with Down syndrome.
For the women taking part in the study, a total of 48 pregnancies with Down syndrome were eventually confirmed with either chorionic villus sampling, or with amniocentesis. Of these, 29 percent were also detected by testing for hCG, 25 percent by testing for the hCG free beta subunit, and 42 percent by protein A. By combining the results of either the hCG test or the free beta subunit tests with the protein A tests, accuracy increased. The detection rate for hCG and protein A tests combined was 63 percent, and the detection rate for the beta subunit and protein A combined was 60 percent. Thus, this screening procedure permits identification of over 60 percent of women carrying Down syndrome fetuses in the first trimester.
Dr. Haddow noted that the blood test is not meant to replace conventional diagnosis with CVS or amniocentesis, but to identify a relatively small group of women who would be considered candidates for those diagnostic procedures.
"Our study provides evidence that first-trimester screening of maternal serum to determine the risk of fetal Down syndrome is feasible when serum pregnancy associated protein A concentrations are used in combination with the concentration of either hCG or its free beta subunit," the researchers concluded.
The study also found that in the first trimester, the rates for detection of Down syndrome were low for both serum alpha-fetoprotein (17 percent) and unconjugated estriol (4 percent).
NICHD's booklet, Facts About Down Syndrome, is available from the publications page of the NICHD website, at www.nih.gov/nichd/, or from the NICHD public information and communications branch, 31 Center Drive, MSC2425, Building 31, Room 2A32, Bethesda, MD 20892-2425. The telephone number is 301-496-5133.